GMP Cell and Gene Therapy

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The Main Department of GMP Cell and Gene Therapy operates Fraunhofer IZI's three modern GMP facilities consisting of ten separate clean room suites (altogether 21 clean room grade B manufacturing rooms) which have been specially optimized for manufacturing of cell and gene therapy products, so called Advanced Therapy Medicinal Products – ATMP. The particular specialty of the about 130 highly qualified staff members is the GMP-compliant manufacturing and quality control of investigational medicinal products.

GMP-compliant process and quality control development as well as the creation of Standard Operating Procedures (SOPs) are intensively discussed with the project partner before being implemented. The leading staff in charge has many years of experience in designing GMP-processes in the cell therapy area.

Manufacture of investigational medicinal products for a gene therapy to treat HIV infections

As part of a clinical trial conducted by the University Medical Center Hamburg-Eppendorf (UKE) together with the Heinrich Pette Institute at the Leibniz Institute for Experimental Virology (HPI), investigational drugs to be used as part of an innovative gene therapy will be manufactured in the GMP clean room facility at Fraunhofer IZI in future.

The procedure was developed by researchers from the HPI and TU Dresden university. It uses molecular genetic scissors (dubbed Brec1) to cut the exact provirus out of the genome of hematopoietic stem cells by means of “genome editing”. This procedure is expected to permanently eradicate HIV from patients, with few adverse effects. [Link] After having clarified the majority of questions pertaining to the activity and toxicity of the procedure in preclinical experiments, the results now have to be corroborated in clinical trials on HIV patients.

The process transfer began at Fraunhofer IZI in February 2019, ensuring that the genetically modified hematopoietic stem cells can be manufactured under GMP conditions and pursuant to the regulatory requirements placed on pharmaceutical production. After obtaining manufacturing authorization in accordance with Section 13 of the German Medicinal Products Act (AMG), the first investigational drugs are expected to be released to the UKE in 2020.

Manufacture of Kymriah®

CAR-T cell therapy is a new type of cancer immunotherapy that uses the patient’s own T cells to fight certain types of cancer. In order to do this, the cells are extracted in the clinic by leukapheresis and then genetically reprogrammed in vitro in such a way that they can use a chimeric antigen receptor (CAR) to recognize cancer cells and other cells that have a special antigen on their surface. Following lymphodepleting chemotherapy, the reprogrammed cells are administered to the patient though an infusion. They then proliferate and can trigger the immune response.

In August 2017, the first CAR-T cell therapy became available in the USA in the form of Kymriah® (CTL019 / tisagenlecleucel). Kymriah® was granted FDA approval for children and young adults aged up to 25 years old diagnosed with acute lymphocytic B-cell leukemia (ALL) who are not responding to the usual therapies or have already suffered relapses. In May 2018, approval was also granted for adult patients with diffuse large B-cell lymphoma (DLBCL) who had suffered relapses after two or more lines of systemic therapy or who have not responded to therapy at all. On August 27, 2018, Novartis announced that it had received approval from the European Commission for both these indications.

Fraunhofer IZI has long since been a key manufacturing and development site for this innovative CAR-T cell therapy for various clinical trials throughout Europe. Over the next few years, prescription-only, approved T-cell therapies will also be manufactured on an interim basis in the Main Department of GMP Cell and Gene Therapy at Fraunhofer IZI, alongside investigational medicinal products. Following a one-year technology transfer period from Novartis’ Morris Plains site in New Jersey, USA, and after obtaining manufacturing authorization in accordance with Section 13 of the German Medicinal Products Act (AMG), the first clinical batch was manufactured at Fraunhofer IZI in Leipzig in August 2016. The Main Department of GMP Cell and Gene Therapy has continuously produced CAR-T cell therapies for Novartis ever since.

Until the end of 2018, batches in the high double-digit range were delivered to patients, including many children, all across Europe. The extremely complex process involved in manufacturing a cell preparation takes several days and involves not only state-of-the-art instrument engineering, but also manual tasks. Before being cleared for human use, extensive analytical release tests are first conducted on the finished product (e.g. concerning identity, purity, in vitro efficacy, microbiological safety) and the batch documentation is reviewed in detail.

With "Sleeping Beauty" against cancer

The US American Food and Drug Administration FDA approved for the first time in 2017 a gene therapy with so-called CAR-T cell therapy. Clinical studies of cancer diseases show that impressive success has already been achieved in the treatment of cancer using this form of therapy. This revolutionary therapy is also the focus of a research project that the PoC initiative will be supporting with about 2.8 million euros. The chimeric antigen receptors (CAR) developed at the University Hospital of Würzburg detect a certain molecule (ROR1), which is barely present in healthy cells, but which occurs all the more on cancerous cells from leukemia, breast or lung cancer. In the case of the research project now being funded by the PoC initiative, the non-viral gene transfer takes place by means of the so-called "Sleeping Beauty" transposon system (SB100X). The funding is to be used to complete pre-clinical studies on the safety and efficacy of the ROR1 CAR-T cells and to achieve the clinical translation into a Phase I study (First-in-Man).

Thy project is funded by the Proof-of-Concept initiative. The initiative was instituted by the Helmholtz Association, the Fraunhofer-Gesellschaft and the German university medical departments, to promote translation of innovative, promising research projects into clinic.

The Main Department GMP Cell and Gene Therapy of Fraunhofer is collaborating with Iovance Biotherapeutics Inc. (San Carlos, CA, USA) on the technology transfer and subsequent continuous manufacturing of allogeneic feeder cells used in Iovances’ Tumor Infiltrating Lymphocyte manufacturing process. This collaboration supports Iovance’s upcoming European clinical trials for the treatment of solid tumors in metastatic melanoma and cervical carcinoma.

Iovance Biotherapeutics, Inc. is a clinical-stage biotechnology company focused on the development of cancer immunotherapy products for the treatment of various cancers. The Company's lead product candidate is an adoptive cell therapy using tumor-infiltrating lymphocyte (TIL) technology being investigated for the treatment of patients with metastatic melanoma, recurrent and/or metastatic squamous cell carcinoma of the head and neck and recurrent and metastatic or persistent cervical cancer. For more information, please visit www.iovance.com.

Development of an additive production platform for biodegradable, patient-specific breast implants for natural breast tissue reconstruction

Breast cancer is one of the most common forms of cancer among women. A mastectomy, i.e. the removal of the breast, is often recommended as part of cancer treatment. Many women who opt for this procedure have to deal not only with the physical consequences of surgery but also, in the longer term, with a huge amount of psychological stress. In Germany, measures taken to restore the breast form part of one of the most common surgical reconstruction procedures. Traditional reconstruction measures, however, continue to be accompanied by countless complications and side effects, including severe fibrotic reactions to exogenous implants, the emergence of capsular contracture that gives the breast an unnatural appearance and also tissue loss. This results in more stress for the patient and the need for additional, costly corrective surgery.

The company BellaSeno GmbH is working with partners to develop an innovative procedure that avoids the above-listed drawbacks of breast reconstruction while restoring the breast tissue in a natural way. In order to do this, state-of-the-art 3D manufacturing processes are combined with established biocompatible materials and surgical techniques.

With the help of 3D laser scanning, the patient's breast area is first evaluated and measured. Software is then used to turn these measurements into a computer model which the treating physician can use to model the implant. Finally, a 3D bioprinter produces the implant using medical grade polycaprolactone (mPCL) – a biodegradable polymer already used in various kinds of surgical applications. These novel implants are placed in the body in exactly the same way as conventional products. The porous structure encourages the surrounding tissue to form blood vessels. This approach is complemented by an autologous fat transfer procedure (injecting the patient's own fat under the skin). Tissue regeneration is stimulated; firstly, as the implant's pores give the adipose cells plenty of space and dimensional stability and, secondly, because the vascularization gives cells a direct nutrient supply. The scaffold gradually degrades as the tissue regenerates, ultimately being replaced with natural breast tissue.

Various development stages are yet to be completed before this procedure can be applied to patients. BellaSeno GmbH is being supported here by the Fraunhofer Institute for Cell Therapy and Immunology. The institute is responsible for evaluating safety in accordance with ISO 10993 and for developing a clean-room based ISO 13485 compliant manufacturing process for the production of BellaSeno implants. Dresden-based company GeSim mbH will further develop the manufacturing technology with an eye to optimizing production rate and capacity. Leipzig University is also involved in the project, carrying out preclinical, long-term studies to review the toxicology and biocompatibility of the implants, while their mechanical properties are being simulated and validated by the company Leichtbau-Zentrum-Sachsen GmbH.

The project has received funding from the Sächsische Aufbaubank (Saxon Development Bank, SAB), using funds from the European Regional Development Fund (ERDF). The Saxon cooperation project aims to have obtained manufacturing authorization for the product by 2020. The project will then move into the clinical trial stage, where the first patients could receive the implants.

Obtaining of a manufacturing authorization for CardAP-Cells

The Department of GMP Cell and Gene Therapy performs together with the Charité-Universitätsmedizin Berlin (Tissue Engineering Lab) and the Berlin-Brandenburg Center for Regenerative Therapies the GMP-process development for manufacturing and quality control of autologous heart muscle derived CardAP-cells. It’s the intention to investigate safety and efficacy by performing clinical trials in the field of chronic myocardial failure. Obtaining a manufacturing authorization according to section 13 German Drug Law is the first project goal.

Cooperation partners

Charité-Universitätsmedizin Berlin, Tissue Engineering Laboratory

Berlin-Brandenburg Center for Regenerative Therapies

Finished Projects

Manufacturing DCVax®-L for the American biotech company Northwest Biotherapeutics, Inc.

Class A (100), B (100), C (10,000), and D (100,000) pharmaceutical clean rooms with a total area of about 1000 sqm, modular structure, divided into suites with separate air filtration. We offer altogether 21 class B manufacturing rooms within three separate clean room facilities for handling different kinds of manufacturing projects for cell and gene therapy products. If required the rooms can be operated according to gene technology safety level S2.